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Article http://pubs.acs.org/journal/acsodf
Photodegradable Coordination Polymer Particles for LightControlled Cargo Release Ying Zhang, Yijun Guo, Siyao Wu, Haojun Liang, and Hangxun Xu* CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China S Supporting Information *
ABSTRACT: Stimuli-responsive coordination polymer particles (CPPs) show great promise for encapsulating and releasing cargos due to their unique and highly tailorable structures and properties. In particular, photoresponsive CPPs have received enormous interest, as noninvasive light can be spatially and temporally controlled, resulting in great safety and efficiency. In this work, we report the design and synthesis of novel photodegradable CPPs by infinite coordination polymerization of Zn2+ and a photocleavable organic linker containing o-nitrobenzyl derivatives. We further demonstrate that these novel photodegradable CPPs are able to efficiently encapsulate cargos and are applicable for on-command drug release upon low-power UV light irradiation (5.78 mW/cm2). Because light is a highly desirable remote-trigger and can be used externally, we expect that these photodegradable CPPs can provide a unique platform for controlled cargo release.
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INTRODUCTION Coordination polymer particles (CPPs) have recently emerged as a new class of functional materials, with various potential applications in catalysis, gas storage, sensing, and molecular electronics.1−10 CPPs have also proven to be able to efficiently encapsulate and deliver various cargos, such as drugs,11,12 organic dyes,13,14 and inorganic nanoparticles,15,16 in their coordination networks. Previously, the release of drugs/cargos from CPPs was primarily diffusion controlled.11,17 Thus, to control the release kinetics, there is growing interest in introducing functionalities into CPPs to develop stimuliresponsive CPPs, which can respond to specific triggers.18,19 However, stimuli-responsive CPPs that are able to change their structures or properties in response to external stimuli such as light, temperature, pH, or chemicals for on-command cargo release are still limited.20−22 Among various external triggers that are being explored in constructing stimuli-responsive CPPs, light is of particular interest, as it only requires simple manipulation and in principle can conveniently offer both temporal and spatial control.23−28 So far, developing CPPs that are able to degrade and release the encapsulated cargos upon light irradiation has still remained a great challenge. Because CPPs are constructed from metal ions and polydentate organic ligands,29−32 an attractive approach to synthesize photoresponsive CPPs is by incorporating photoresponsive organic ligands into the coordination network. In this context, o-nitrobenzyl derivatives, which can undergo efficient photocleavage reactions under UV light (λ = 365 nm) irradiation, are ideal candidates for synthesizing photoresponsive CPPs. In particular, the photolysis of o-nitrobenzyl © 2017 American Chemical Society
is an intermolecular rearrangement process, which does not require protonic solvents and can readily occur both in solution and the solid state.33 More importantly, the photocleavage of onitrobenzyl derivatives can be triggered using low-power UV light, which is a distinct feature required for biological applications because low-power UV light causes less photodamage to biological tissues and cells.34 Therefore, considering their interesting properties and potential applications as delivery carriers, CPPs containing o-nitrobenzyl groups could be very promising for light-controlled cargo release. Here, we report the design and synthesis of novel photodegradable CPPs by infinite coordination polymerization of Zn2+ and a photocleavable organic linker containing onitrobenzyl derivatives. We further demonstrate that these photodegradable CPPs are able to efficiently encapsulate cargos and are applicable for on-command drug/cargo release upon the irradiation of low-power UV light (λ = 365 nm, 5.78 mW/ cm2). The entire process is illustrated in Scheme 1a. We believe this proof-of-concept research not only represents a simple approach to prepare stimuli-responsive CPPs but may also provide a unique coordination-based system for on-command drug delivery.
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RESULTS AND DISCUSSION In this approach, the key to achieve photodegradable CPPs is to incorporate the o-nitrobenzyl group into polydentate organic Received: April 12, 2017 Accepted: May 26, 2017 Published: June 7, 2017 2536
DOI: 10.1021/acsomega.7b00440 ACS Omega 2017, 2, 2536−2543
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Scheme 1. (a) Synthesis of Photodegradable CPPs and Chemical Structure of the Photocleavable Organic Ligand Used in Their Synthesisa
a
(a) Schematic illustration of the synthesis of photodegradable coordination polymer particles (CPPs). The cargos can be encapsulated in CPPs for a light-controlled release via photolysis of the organic linkers. (b) Chemical structure of the photocleavable organic ligand used in the synthesis of CPPs and cleavage of the ligand under UV light irradiation.
ligands. Therefore, we first designed and synthesized a novel photocleavable coordination ligand containing the o-nitrobenzyl functional group, (2-nitro-1,3-phenylene)bis(methylene)bis(1H-imidazole-1-carboxylate) (Scheme 1b, hereafter referred to as NPMIC). The detailed synthetic procedures for NPMIC can be found in the Experimental Section. The chemical structure of the NPMIC was confirmed by both 1H and 13C NMR spectra (Figures S1 and S2). Because of the fast response of the o-nitrobenzyl group, the photocleavage reaction was efficient in the NPMIC ligands, simultaneously releasing free carboxylic acids and aromatic aldehydes (Scheme 1b).35 The photolysis products of the NPMIC ligands were detected by electrospray ionization mass spectrometry (ESI-MS) (Figure S3), suggesting that the NPMIC ligands can be used as photocleavable coordination ligands in CPPs. The photodegradable CPPs can be conveniently synthesized by coordination between Zn2+ and NPMIC ligands (1:1 molecular ratio) at room temperature (hereafter referred to as the ZnNPMIC particles). The resulting ZnNPMIC particles were then purified by centrifugation and washed several times with ethanol. The diameters of these as-synthesized particles can be controlled from ∼160 to 1500 nm using different concentrations of the precursor solutions (from 0.1 to 0.001 M) as shown in the transmission electron microscopy (TEM) images (Figure 1a−c). The average sizes of the ZnNPMIC particles were also determined using dynamic light scattering
(DLS) measurements, confirming that the particle sizes can be controlled by varying the concentrations of the Zn ions and NPMIC ligands (Figure 1d). Powder X-ray diffraction (PXRD) patterns (Figure S4) indicated that these ZnNPMIC particles were amorphous. Selected area electron diffraction (SAED) patterns of a typical ZnNPMIC particle also revealed that these coordinatively formed particles were amorphous (Figure 1e,f). Furthermore, EDX mapping results (Figure 1g) demonstrated that both zinc and nitrogen were homogeneously distributed over the particle, implying that both Zn2+ and NPMIC ligands were uniformly coordinated to form the coordination particles. The Fourier transform infrared (FTIR) spectrum confirmed the coordination of the NPMIC ligands to the Zn ions, as the peak at 623 cm−1 is the characteristic peak of the Zn−N bond (Figure 2a).36 The photodegradation of these ZnNPMIC particles (∼550 nm) upon irradiation by low-power UV light at 365 nm can be revealed by the FTIR results. Obviously, the ester bond at 1756 cm−1 was cleaved and the intensity of the peak diminished after photoirradiation (Figure 2a). Meanwhile, the C−H stretching vibration peaks at 2920 and 2850 cm−1 and the CO stretching vibration peak at 1645 cm−1 of the aldehyde groups appeared. Moreover, the CO stretching peak at 1720 cm−1 corresponding to the carboxylic group also emerged, indicating the cleavage of the ester bond and formation of aldehydes and carboxylic acids upon photoirradiation (Scheme 1b).35 As shown in Figure 2b, increased absorption over a wide range of wavelengths in the 300−400 2537
DOI: 10.1021/acsomega.7b00440 ACS Omega 2017, 2, 2536−2543
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Figure 1. (a−c) TEM images of ZnNPMIC particles with different sizes using precursor solutions with different concentrations: (a) 0.001 M, (b) 0.05 M, and (c) 0.1 M. (d) DLS measurements of ZnNPMIC particles with different average diameters ((1480 ± 90) nm, (540 ± 60) nm, and (160 ± 13) nm). (e) TEM image of a single ZnNPMIC particle. (f) SAED pattern of the ZnNPMIC particle shown in (e). (g) HAADF-STEM image of a ZnNPMIC particle and the corresponding elemental mapping of N and Zn.
encapsulation of fluorescein into these particles was confirmed by UV−vis absorption measurement, and the loading efficiency was determined to be 9% (see Experimental Section for details). The UV−vis result also showed the distinction between the fluorescein and the ZnNPMIC particles (Figure S5). As shown in Figure 3a, the fluorescein@ZnNPMIC particles still maintained their spherical structure. Meanwhile, no dramatic variation in the particle size could be found from DLS measurements (Figure S6). Only ∼17% of fluorescein was released in aqueous solutions for over 45 h without photoirradiation at room temperature (Figure 3b), suggesting that these ZnNPMIC particles are relatively stable, and only a small fraction of dyes diffused into the solution. In sharp contrast, the release rate was significantly increased and nearly 100% release of fluorescein was achieved for only 15 h under UV light irradiation, demonstrating that these ZnNPMIC particles are highly efficient for light-controlled cargo release. In addition, the size of the ZnNPMIC particles also affected the release rates of cargos. For example, we investigated the release of fluorescein from ZnNPMIC particles with different sizes and
nm range was observed after UV irradiation. This can be attributed to the photocleavage of o-nitrobenzyl moieties and formation of species of various sizes containing nitrosobenzyl and residual nitrobenzyl units.37 The degradation of the ZnNPMIC particles under photoirradiation was further confirmed by the DLS measurements. The average diameters of these particles at different time intervals of UV irradiation decreased from 550 to 220 nm (Figure 2c), implying that the CPPs were degraded via photolysis of the bridging ligands. Further examination of the ZnNPMIC particles under short UV irradiation (∼10 min) revealed that the degradation of the ZnNPMIC particles was heterogeneous as it can be seen that the particle contained multiple holes of different sizes (Figure 2d). CPPs are known to be able to encapsulate and release cargos, although the releasing process was mainly diffusion controlled in previous reports.11,17 To investigate the application of the ZnNPMIC particles for the light-controlled cargo release, we first studied the encapsulation and release of fluorescein in the ZnNPMIC particles (average diameter ≈550 nm). The 2538
DOI: 10.1021/acsomega.7b00440 ACS Omega 2017, 2, 2536−2543
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Figure 2. (a) FTIR spectra of ZnNPMIC particles (∼550 nm) before and after UV irradiation. (b) UV−vis absorption spectra of ZnNPMIC particles (∼550 nm) under different durations of UV irradiation. (c) DLS results of the ZnNPMIC particles (∼550 nm) under different durations of UV irradiation. (d) TEM image of a ZnNPMIC particle after UV irradiation for 10 min.
Figure 3. (a) TEM image of the ZnNPMIC particles (∼550 nm) encapsulated with fluorescein. (b) Release profiles of fluorescein from fluorescein@ ZnNPMIC particles at room temperature, with and without UV light irradiation.
particles are relatively stable under physiological conditions. The much higher release efficiency in TCN is likely caused by the smaller molecular size of TCN molecules, which can lead to a faster diffusion rate.40 Upon UV light irradiation, however, an accelerated release rate was observed. Approximately 90 and 89% of TCN and DOX were released into the PBS solutions, respectively. These results revealed that the photoresponsive onitrobenzyl groups played a critical role in light-controlled drug release. The efficient encapsulation and release of drugs using photodegradable ZnNPMIC particles was further investigated by in vitro cytotoxicity assays on HeLa cells using DOX@ ZnNPMIC particles. As shown in Figure 4c, the as-prepared DOX@ZnNPMIC particles can be taken up by HeLa cells
the results indicated that larger ZnNPMIC particles exhibited much faster release kinetics (Figure S7). On the basis of the above results, we then employed these ZnNPMIC particles for potential drug delivery. TCN, an antibiotic agent, and doxorubicin (DOX), a known anticancer drug, were used as model drugs for this purpose.38,39 The encapsulation was completed during the formation of ZnNPMIC particles, with sizes of around ∼200 nm (Figure S8). The loading efficiency was determined to be ∼10 and 9% for TCN and DOX, respectively. The light-triggered release was taken out in phosphate-buffered saline (PBS) solutions at pH 7.4 (37 °C). The release amounts of TCN and DOX from ZnNPMIC particles suspended in PBS were less than 42 and 23% for over 20 h, respectively, indicating that the ZnNPMIC 2539
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Figure 4. In vitro release profiles of TCN and DOX from (a) TCN@ZnNPMIC and (b) DOX@ZnNPMIC particles, with and without UV light irradiation. The duration of light irradiation was 60 min. (c) Confocal microscopy image of HeLa cells following incubation with ∼200 nm DOX@ ZnNPMIC particles (1 μg/mL) for 6 h. (d) In vitro cytotoxicity assay curves after incubating HeLa cells with various samples at 37 °C for 48 h. Error bars denote standard errors of means from three independent experiments.
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CONCLUSIONS In conclusion, we have designed and synthesized novel photodegradable CPPs and explored their photoresponsive properties for light-controlled cargo release. The photodegradable CPPs were achieved by incorporating the onitrobenzyl functional group into the bridging organic ligands. We show that low-power UV light can trigger the degradation of the CPPs, as observed by significant changes in the hydrodynamic sizes, with different UV exposure times. More importantly, these photodegradable CPPs are able to encapsulate organic dyes and drugs and release them in response to light, implying that they can be used as functional carriers for delivering therapeutic cargos in the future. Because light is a highly desirable remote-trigger and can be used externally, we expect that these photodegradable CPPs can provide a unique platform for controlled/targeted release of other cargos. Our study also indicates that stimuli-responsive CPPs can be achieved by designing new polydentate bridging ligands with new functionalities.
possibly via internalizing through the endocytosis mechanism.41,42 Treatment of HeLa cells with bare ZnNPMIC particles, with or without low-power UV light irradiation, will not lead to any appreciable cell death after 48 h (Figure S9). At low DOX uptake concentrations (
